TNF-.alpha. is a protein which is produced from certain cells, including, for example, T cells, macrophages, and natural killer cells, by induction with prophlogistic agents such as bacteria, viruses, various mitogens or the like, and has the biological activities as described below:
1) a factor inducing hemorrhagic necrosis in tumors (in vivo), PA1 2) induction of apoptosis in cancer cells (in vitro), PA1 3) production of prostaglandins and collagenase, PA1 4) expression of adhesion molecules (ICAM-1, ELAM-1), PA1 5) expression of HLA class II, PA1 6) production of inflammatory cytokines (IL-1, IL-6), PA1 7) production of chemokines (IL-8, RANTES), and PA1 8) enhancement of absorption of bone and cartilage. PA1 1) a change from cytosine (C) to thymine (T) at position -857 (position 373 in SEQ ID NO: 9), PA1 2) a change from cytosine (C) to adenine (A) at position -863 (position 367 in SEQ ID NO: 9), PA1 3) a change from thymine (T) to cytosine (C) at position -1031 (position 199 in SEQ ID NO: 9), and PA1 4) respective changes corresponding thereto in the complementary strand.
TNF-.alpha. is believed to be an important agent that is located at most upstream in pathogenetic cytokine cascades of various inflammatory diseases.
Individual differences in amount of production of TNF-.alpha. have been previously pointed out. In addition, TNF-.alpha. is an important cytokine that is involved in vascular disorders. In the acute phase of Kawasaki disease, TNF-.alpha. exhibits an abnormally high level in serum, and it is said that the amount of production of TNF-.alpha. is enhanced in peripheral blood monocytes in this phase. These facts suggest that TNF-.alpha. plays an important role in onset of Kawasaki diseases of which major lesion is systemic vascular disorders (M. Sakaguchi, H. Kato, A. Nishiyori, K. Sagawa and K. Itho, Production of tumor necrosis factor-alpha by V.beta..sup.2- or V.beta.8.sup.- CD4.sup.+ T cells in Kawasaki disease in "Kawasaki disease" (H. Kato, Ed.), pp. 206-213, Elsevier, Amsterdam (1995)). It is thus expected that increased amount of TNF-.alpha. production based on genetic factors may be involved in onset and severity of Kawasaki disease.
Similarly, production of TNF-.alpha. is also enhanced in rheumatism (M. Sebbag, S. L. Parry, F. M. Brennan and M. Feldmann, "Cytokine stimulation of T lymphocytes regulates their capacity to induce monocyte production of tumor necrosis factor-alpha, but not interleukin-10: possible relevance to pathophysiology of rheumatoid arthritis", Eur. J. Immunol. 27:624-632 (1997)).
On the contrary, the capacity to produce TNF is said to be low in SLE nephropathy (C. 0. Jacob, Z. Fronek, G. D. Lewis, M. Koo, J. A. Hansen and H. 0. McDevitt, "Heritable major histocompatibility complex class II-associated differences in production of tumor necrosis factor c: Relevance to genetic predisposition to systemic lupus erythematosusf Proc. Natl. Acad. Si. USA, 87:1233-1237 (1990)).